ABSTRACT Surgical site infections (SSIs) are now the most common group of healthcare associated infections (HAIs) and are a significant cause of preventable morbidity and mortality in the United States. These infections result in significant patient suffering and excess health care costs up to $10 billion each year. For these reasons, their prevention is a top priority for the U.S. Department of Health and Human Services and the Institute of Medicine. Although several initiatives target HAIs, few are directed at SSIs after cesarean despite the fact that cesarean is the most common major surgical procedure performed in women. The Prophylactic Negative Pressure Wound Therapy in Obese Women at Cesarean Trial is a large pragmatic multicenter randomized clinical trial designed to evaluate the effectiveness, safety and cost-effectiveness of prophylactic negative pressure wound therapy (NPWT) ? a closed, sealed system that applies negative pressure to the wound surface via a single-use, battery-powered, portable device ? to decrease surgical site infections (SSIs) in obese women undergoing cesarean delivery. Experimental evidence suggests that NPWT promotes wound healing by removing exudate, approximating the wound edges, and reducing bacterial contamination. Obesity increases the risk for both cesarean delivery and SSIs compared to non-obese women. The increased risk is in part due to the increased thickness of the subcutaneous space, allowing collection of exudates and increasing tension on wound edges, promoting the growth of bacteria, and leading to wound infection and breakdown. Thus, prophylactic NPWT may be particularly effective in this patient population. During the 5-year project period, a multidisciplinary team of investigators from 4 collaborating perinatal centers (two university and two community) representing two regions of the U.S. with high rates of maternal obesity will randomize 2,850 obese women undergoing cesarean delivery to receive either prophylactic NPWT with the PICOTM device or standard wound dressing. The specific aims of the project are: 1) Determine the effectiveness of prophylactic NPWT in reducing the rate of SSIs after cesarean in obese women (Primary Aim), 2) Assess the safety of prophylactic NPWT in obese women as measured by frequency of adverse events including skin blisters, erythema, and wound bleeding (Secondary Aim#1), and 3) Evaluate the cost-effectiveness of prophylactic NPWT compared with standard wound dressing in obese women as measured by the incremental cost per case of SSI prevented and per Quality-adjusted Life-year (Secondary Aim#2). The expected outcome of this study is high-quality, readily applicable, evidence on the effectiveness, safety, and cost-effectiveness of prophylactic NPWT in reducing SSIs after cesarean in obese women. If proven effective, use of this simple device in obese women, who are at high risk for both cesarean delivery and subsequent SSIs, will have an important positive impact on post- cesarean morbidity and associated healthcare costs.